What are the established risks of long-term zopiclone (non-benzodiazepine hypnotic) use?

Established Risks of Long-Term Zopiclone Use

Long-term zopiclone use carries significant risks including dependence, withdrawal symptoms, tolerance, cognitive impairment, and increased risk of falls, which outweigh potential benefits beyond short-term use. 1, 2

Primary Risks

Dependence and Withdrawal

• Physical and psychological dependence can develop with prolonged use 2
• Withdrawal symptoms may include:
  • Anxiety
  • Abnormal dreams
  • Hyperesthesia
  • Neurosis
  • Rebound insomnia (temporary worsening of sleep parameters)
  • In severe cases: palpitations, sweating, irritability, hallucinations, and impulsive behavior 3

Tolerance

• Diminished effectiveness over time requiring increased dosages 2
• Clinical data on tolerance development are conflicting, with some studies showing no development of tolerance over 4-week periods, while longer-term studies suggest tolerance may develop 4

Cognitive and Psychomotor Impairment

• Morning-after effects including:
  • Reduced concentration
  • Impaired memory
  • Decreased psychomotor function (especially within 4-5 hours of dosing) 2
• Confusion and memory impairment more common in elderly patients 2

Sleep-Related Behaviors

• Risk for serious injuries from complex sleep behaviors:
  • Sleepwalking
  • Sleep driving
  • Other activities while not fully awake 1

Additional Risks

Falls and Injuries

• Increased risk of falls, particularly in elderly patients 5
• Heightened risk when combined with other sedating medications 5

Abuse Potential

• Schedule IV controlled substance with abuse potential similar to benzodiazepines 2
• Higher risk in patients with history of substance abuse 6
• Case reports document extreme cases of abuse (doses up to 112.5 mg/day, 15 times the recommended dose) 3

Drug Interactions

• Dangerous respiratory depression when combined with opioids 1
• Cumulative and synergistic effects on respiratory depression when combined with benzodiazepines 1

Clinical Implications

Recommended Duration

• Zopiclone should be prescribed for short-term use only (≤4 weeks) 7
• Long-term use is not recommended by clinical guidelines 1, 5

Discontinuation Protocol

• Gradual tapering is necessary to prevent withdrawal symptoms 2
• Withdrawal effects are typically mild and resolve within 1-2 nights after discontinuation 2
• More severe cases may require supervised withdrawal with substitute medications 3

Monitoring Considerations

• Regular assessment for signs of dependence and tolerance
• Evaluation of continued efficacy
• Monitoring for cognitive and psychomotor impairment, especially in elderly patients

Alternative Approaches

• Cognitive Behavioral Therapy for Insomnia (CBT-I) is strongly recommended as first-line treatment for chronic insomnia 1, 5
• If medication is necessary, it should be administered at the lowest effective dose for the shortest possible duration 1
• All patients should receive counseling about potential risks of zopiclone 1

While zopiclone was initially believed to have advantages over benzodiazepines in terms of dependence and withdrawal risk, clinical experience over time has shown that its long-term safety profile is concerning and similar to benzodiazepines in many respects 1, 8.